Spinal cord injury (SCI) leads to severe impairments in locomotor and somatosensory function. Alterations in somatosensation include central neuropathic pain (CNP) which persists for the patient's life. CNP occurs in the majority of SCI patients, so adversely affecting the quality of life that suicide frequently ensues. This is a major, poorly understood, public health problem and understanding the mechanisms underlying CNP should lead to opportunities for intervention to prevent this terrible condition. Our overall goal is to identify mechanisms contributing to CNP following SCI. We use the rodent spinal cord contusion model since this model best approximates human SCI. CNP in this model includes above level (forelimb), at level (trunk) and below level (hindlimb) pain-like behaviors that resemble those seen in human SCI. The dogma is that spinal mechanisms give rise to CNP, generated by increased extracellular glutamate at the time of contusion. Our preliminary data, however, show that mechanical and thermal sensitization occurs in primary afferent nociceptors in the intercostal nerves (at level) and in the forelimbs (above level), the latter being a location where there is no damage to either the spinal cord or peripheral nerves. Our hypothesis is that a reverberating loop is set up beginning with injury-induced release of glutamate in the cord. The glutamate generates dorsal root reflexes (DRRs) that cause peripheral neurogenic inflammation (from release of neuropeptides peripherally). The neurogenic inflammation leads to peripheral sensitization of primary afferent fibers which sensitizes dorsal horn neurons. Once this reverberating loop is established, it is maintained chronically. In support of this hypothesis, our preliminary data demonstrate the presence of abnormally high DRR activity in cervical afferents in SCI rats compared to controls. The discharge rate of spontaneous DRRs in C and A5 fibers is significantly elevated in SCI cervical afferents, the percentage of A5 fibers with evoked DRRs is increased and these are reduced by intrathecal bicuculline, a GABAA antagonist. These data provide a critical link between the spinal cord (the site of injury) and the peripheral afferents. Our specific hypothesis is that primary afferents contribute to the central sensitization underlying CNP, and blocking DRRs and/or peripheral sensitization will attenuate CNP. To test this hypothesis, aim 1 will determine the time course of peripheral and central sensitization following SCI;aim 2 will demonstrate that treatment of SCI rats with glutamate antagonists reduces CNP, evidenced by reduced pain behaviors, attenuation of both peripheral and central sensitization and decreased DRRs. Conversely, treatment of naive rats with intrathecal glutamate will produce these signs of CNP. Aim 3 will demonstrate that blocking DRRs will attenuate central and peripheral sensitization and neurogenic inflammation. In this proposal we will elucidate mechanisms that heretofore have been unknown contributors to central neuropathic pain.